EI Risk Assessment
Elemental Impurity Risk Assessment Case StudiesAuthor: Andrew Teasdale and Laura Rutter (on behalf of EFPIA)Date: 5 April 2016 * Version: Finalwww.efpia.eu1
OverviewUsing the principles outlined in ICH Q3D and training modules we will: Present a series of risk assessments based on actual products. Examining different routes of administration. Through this seek to highlight there is more than one approach,illustrated through the examples shown. Marketing application – example summary and proposed location. Approach to products during clinical development.www.efpia.eu2
ICH Q3D Guideline for Elemental Impurities –Practical Implementation of ICH Q3D ICH Q3D recommends taking a risk based approach. Focus is on the final product – the fishbone diagram assists by advising on the components forconsideration: all potential sources of elemental impurities should be considered and evaluated for theircontribution to the drug product. The product assessment will form the basis of a specific control strategy for EIs and should be available tobe presented to Regulators during an inspection upon request. An industry position paper has been jointly authored and published in PharmTech.DrugSubstanceMore Likely SourcesExcipientsElementalImpurities inDrug ProductManufacturingEquipmentUtilities (e.g.,Water)–ContainerClosureSystemLower Riskwww.efpia.eu3
Risk Process – General PrinciplesIdentify Review API, excipient and drug productmanufacturing process to identify knownand potential sources of ElementalImpuritiesEvaluate Collect predicted and/or observed levels ofelemental impurities Compare data with the establishedPermitted Daily ExposureSummarizeControl Summarize and document the riskassessment Identify additional control requirements, ifrequired, to ensure PDE is met ICH Q3D advocates a 3 step process: Identify Evaluate Summarize Control Different approaches to each stage are nowexamined through a series of actual riskassessments.www.efpia.eu4
Industry Risk AssessmentExample 1Synthetic API – tabletwww.efpia.eu5
Industry Risk AssessmentExample 1 – Oral Solid DoseProductDose FormStrengthTherapeutic Target (Why patients take thisproduct)Dosing Regemine (Frequency & Duration ofdosing)Maximum Daily Dose of ActiveMass of Dosage UnitRoute of AdministrationUSP Monograph for ProductSite of ManufacturePacking SiteElements being EvaluatedClass 1Class 2AClass 2BClass 3Compound XTablet200/ 400 mg compound XOsteoarthritisDaily, one tablet400mg Compound X638.6 mgOralNoGMPGMPCd, Pb, AS, HgCo, V, NiPd – Metal catalyst used in API synthesisSn - HypromelloseAdditional metals identified by riskAssessmentwww.efpia.eu6
Example 1 – OralSolid DoseComponentCoreAPIHypromellose 2910Microcrystalline CelluloseLactose MonohydrateCrospovidoneMagnesium stearateCoatingHypromellose 2910Titanium dioxideTriacetinBlue Aluminium Lake #2Blue Aluminium Lake #1FunctionalityDrug t per % in coated Type (Excipient)400 mg tablet .06Mineral0.030.005Mineralwww.efpia.eu7
Product Information – API SynthesisPRE-RSMOYONHN2H2 PdXXXY''XNBrNHXylenes,140 AlkY''Ni. NaOH, H2Oii. HBr,APIXcf. ICH Q3D: "For biotechnology-derived products, the risks of elemental impuritiesbeing present at levels that raise safety concerns at the drug substance stage areconsidered low.")www.efpia.eu8
Product Information – drug product manufactureFormulation and componentsAPILactoseMicrocrystalline CelluloseCrospovidoneHypromelloseUnit operationsFormulation and componentsCrospovidone Unit operations Stage 6: BlendingStage 1: Dry MixMagnesium stearateDiffusion mixers (tumble)High shear wet granulatorStage 7: Lubrication Stage 2: High Shear Wet GranulationDiffusion mixers (tumble)HypromelloseHigh shear wet granulator PharmacopeialGradePurified waterStage 8: Compression Tablet pressStage 3: Wet Milling Screening MillsFilm CoatStage 4: Fluidised Bed Drying Stage 9: Film CoatingPan coatingDirect heating, fluidised solids bed Stage 10: PackingStage 5: MillingScreening millEvaluation process not just data driven Can be based on first principles.With regards to the process described an evaluation was conducted prior to manufacture Concluded that risk very low given lack of any extremes of pH and low residencetimes. Visual inspection / cleaning also part of GMP.Section 5.2 – Risk can bereduced through processunderstanding / equipmentselection / qualification andGMP processes.www.efpia.eu9
Product Information – packagingDrug Substance packaging Drug substance stored in double low density polyethylene bags individually closed withplastic tie wraps. The closed bags are stored inside a rigid outer container/drum.Drug Product packaging X tablets are presented as blister packs formed from unplasticized polyvinyl chloride(PVC) film laminated to a polychlorotrifluoroethene (PCTFE) and sealed to push-throughblister foilRisk factors: Contact Solid to Solid – no mechanism* Data relating to PE / PVC show very low EI riskSection 5.3 – Probability of elemental leaching into solid dosage forms is minimal anddoes not require further consideration in the risk assessmentwww.efpia.eu10
Step 1 – IdentifyThere are multiple ways to conduct an assessmentIdentify Review API, excipient and drug productmanufacturing process to identify knownand potential sources of ElementalImpuritiesEvaluate Collect predicted and/or observed levels ofelemental impurities Compare data with the establishedPermitted Daily ExposureSummarizeControl Summarize and document the riskassessment Identify additional control requirements, ifrequired, to ensure PDE is met In this example all input materials wererecorded and a specific risk assessmenttool used to evaluate each potential EIsource Using a pre-defined scoring system. This is then represented graphicallycoding risk in terms of red/amber/greenas well as the numerical risk factor.www.efpia.eu11
IdentifyTypical high risks:metal catalysts/reagents,mined excipientsRisks controlled by GMP:purified water,equipment compatibilitywww.efpia.eu12
IdentifyOther factors Any risk assessment needs to be supported by an appropriateEvaluation process not just datadrivenCan be based on first principlesIPEC Questionnaireoverall quality system. Key aspects of this would typicallyinclude: Vendor Assurance Change Control Supplier Information Certificate of Analysis EI risk assessment In this example for Crospovidone the following informationavailable: Pharmaceutical excipient handbook suggests that a catalyst can be usedin the production of crospovidone. Supplier provided a statement to confirm that no metal catalysts areused in the manufacture of their xx grade crospovidone.www.efpia.eu13
Step 2 - Evaluate Based on the risk analysis –Potentialsource of metalimpuritiesNo. of batches to beanalysedHypromellose3 batchesrepresentative of thequality/supplier/grade to be used duringcommercialmanufacturescreening requirements weredefined. Screening focused on Class 1and Class 2A metals Identifiedmetals. Section 5.6 - 3 production or 6pilot scale lots Analysis performed using ‘fit forElemental l impurities to include inanalytical screeningEnvironmentaland naturallyabundantelementsIntentionallyadded’ metals e.g.metalcatalysts/reagentsClass 1: As, Cd,Hg, PbSnClass 2A: V, gnesiumstearateCrospovidone3 batchesNone3 batchesNone3 batchesNoneNoneNoneCoating3 batchespurpose’ methodologySection 9 – The determination of EIs should beconducted using appropriate procedures suitable fortheir intended purposeAPI3 batchesCommentsClass 1: As, Cd,Hg, PbClass 2A: V, Co,NiAddressedthrough detailedsupplierresponseAluminium lakesare used to colourthe coating blue.Pd - catalystwww.efpia.eu14
Step 2 – Evaluate Negligible levels of Class 1 / Class 2A metals across API and excipients testedPotentialsource ofelementalimpuritiesBatchNumberElemental impurity concentration in µg/gAsPbCdHgVCoNiPdBatch 1 0.1 0.1 0.11.8 0.1 0.11.0 5Batch 2 0.1 0.1 0.1 0.1 0.1 0.11.0 5Batch 3 0.1 0.1 0.1 0.1 0.1 0.10.3 5Limit of detection (µg/g)0.10.10.10.10.10.10.15Option 2a target limit µg/g(0.64 g/day drug product)237.87.8471607831016030% Option 2a target limitµg/g7.02.32.31447239447APIwww.efpia.eu15
Step 3 – Summarize Control - ActionsElementAsPbIntentionallyadded(if used in theprocess)NoNoCdNoHgPotentiallyintroduced intodrug substancewith sodiumhydroxideElementalimpurities with arelatively highenvironmentalabundanceNegligible levelsNegligible levelsNegligible levelsNegligible levelsManufacturingequipmentNoNoNoNoLeached bility ofelementalimpuritycontributionYesYesYesYesThe overall risk to Patients is very low.Controlthresholdµg/day (30%PDE)Action4.5no further controlsrequired. See controlsection for summary ofexisting controls1.5no further controlsrequired. See controlsection for summary ofexisting controls1.5no further controlsrequired. See controlsection for summary ofexisting controls9.0no further controlsrequired. See controlsection for summary ofexisting controlswww.efpia.eu16
Summarize Control - ActionsElementalimpurities witha relativelyManufacturingElementequipmenthigh(if used in elevelsPdCatalyst usedpre-RSMNegligiblelevels in seNegligiblelevels suresystemsNoNoNoNoNoAcceptablevariability rolthresholdµg/day(30% PDE)Action30no further controlsrequired. See controlsection for summary ofexisting controls15no further controlsrequired. See controlsection for summary ofexisting controls60no further controlsrequired. See controlsection for summary ofexisting controls30no further controlsrequired. See controlsection for summary ofexisting controls1800no further controlsrequired. See controlsection for summary ofexisting controls.www.efpia.eu17
Summarize ControlThe overall risk to Patients is very low. No requirement for additional control measures has been identified in the evaluatestage. The existing measures adequately control the levels of metal impurities in the drugproductPd catalyst –Pre- ined excipients constitute small % of formulationClass 1 and 2a Els not detected in synthetic / plant /animal derived excipientsElementalImpurities inDrug ProductManufacturingEquipmentUtilities (e.g.,Water)GMP controlContainerClosureSystemSolid dosage formwww.efpia.eu18
Industry Risk AssessmentExample 2Inhaled formulation – dry powderwww.efpia.eu19
Step 1 - IdentifyProductDrug Product Y (DPY)Dose FormDry Powder InhalationStrengthTherapeutic Target (Why patients take thisproduct)Dosing Regemine (Frequency & Duration ofdosing)Maximum Daily Dose of Active500 µgAsthmaOne inhalation once a day; daily500µg of DPY drug substanceMass of Dosage Unit25 mgRoute of AdministrationInhalationUSP Monograph for ProductNoSite of ManufactureManufacturing Site 1Packing SiteManufacturing Site 1Elements being EvaluatedClass 1Cd, Pb, As, HgClass 2ACo, V, NiClass 2BPd, PtClass 3Other ElementsLi, Sb, Ba, Mo, Cu, Sn, CrN/Awww.efpia.eu20
API and ExcipientsProduct Components & SourcesComponentDPY Drug Substance(micronized)Lactose monohydrate,Amount/Unit (mg)0.50024.5Information Available fromSupplierMaxDailyIntake(mg)Percentof RiskAssessmentManufacturingSite 1YesNoVendor AYesNo98Vendor BUnit Weight (mg)25Units per day1Daily Intake theticN/ANaturalAnimalNoSection 5 – The level of effort and formality of the risk assessmentshould be proportional to the level of riskwww.efpia.eu21
Known Information Regarding Elemental Impurity ContentComponentDPY DrugSubstance(micronized)SupplierManufacturingSite 1Vendor AMetalsMetals as Naturally Testing erformed(used in process)Data AvailableCommentsNGT 5ppmNGT 5ppmNGT 20ppmYesYesYesPd & Pt determined by ICPOES on a routine basisYesPd/Ptheterogeneouscatalyst usedNegligible risk Class 1 Class 2A Class 3PdPtUSP 231 NoNegligible risk Class 1 Class 2A Class 3USP 231 NMT 5µg/gOn CoAHeavy Metals testing reportedon COA as limit testNoNegligible risk Class 1 Class 2A Class 3USP 231 NMT 5µg/gOn CoAHeavy Metals testingperformed weekly andreported on COA, limit testLactosemonohydrate,Vendor BCurrent Limitswww.efpia.eu22
Manufacturing EquipmentRisk fromCorrosion,Leaching orChelatingOverallRiskRelative toPDEActionsStepNotes (e.g.Machine type)ContactMaterialRisk fromAbrasion/AttritionBlendingBowl 1StainlessSteelModerateVery LowLowLow Risk – noaction neededFillingEQUIP 1StainlessSteelVery LowVery LowNoneLow Risk – noaction neededwww.efpia.eu23
Utilities/Water Water is not used in the manufacture of Drug Product YDry Powder Inhaler 500 µg. Utilities (such as air) used inthe manufacture of the product will comply toUSP/Ph.Eur. and appropriate Manufacturing Site 1standards. As such, the probability of elemental impurities beingintroduced into the product by the utilities is very low.www.efpia.eu24
Container ClosurePack mentalImpurities?OverallRiskRelative toPDEActionsPolyethylene BagN/APolyethyleneNoNoneNone – used to storeblend before fillingstrips.Lid Foil LaminateN/AHeat SealLacquerYesAluminiumNoneLow Risk – no actionneededBase FoilLaminateN/APVC (PolyvinylChloride)YesAluminiumNoneLow Risk – no actionneededwww.efpia.eu25
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Step 2 - Evaluate – Option 2bTemplate version1.0ICH Q3D, Current Step 4 version, dated 16 December2014 (Option 2b)RiskDocument IDAssessment 2Elemental Impurities Product AssessmentProductFormulationDoses(/day)Drug Product YInhalationComponents12Excipient statements made miumSiteCobaltCompanyBatch / )LeadComponentCadmiumTypeAssess (µg/g)CdPbAsHgCoVNiPdPtLiSbBaMoCuSnCrControl Strategy (see Evaluate section, right)APIDPY DrugSubstance0.5DP CompanyManufacturingSite 1DPY-API 12320ExcipLactoseMonohydrate24.5Vendor ALAC siteLAC 456555Levels for Pb based on PharmacopeialMonograph limitwww.efpia.eu27
Evaluate – Option 2bOption 2b – permitted concentration limitsof elements in individual components of aproduct with a specified intake.Template version1.0ICH Q3D, Current Step 4 version, dated 16 December2014 (Option 2b)RiskDocument IDAssessment 2Elemental Impurities Product AssessmentProductFormulationDoses(/day)Drug Product YTakes into account the amount of eachcomponent in the formulationInhalation1Components2Excipient statements made entCadmiumTypeEvaluate (µg/day)SiteCdPbAsHgCoVNiPdPtLiSbBaMoCuSnCrICH Q3D Permitted Daily Exposure (µg/day)2521315112520300103060330 % Control Threshold inal Evaluated Value (adjusted for luateBatch / LotNumberActual Values (µg/g)(overrides sum evaluation) Override Override Override Override Override Override Override Override Override Override Override Override Override Override Override OverrideAction or No actionAction No action ActionActionActionActionAction No action No action ActionActionActionActionActionActionActionAPIDPY DrugSubstance0.5DP CompanyManufacturingSite 1DPY-API ctoseMonohydrate24.5Vendor ALAC siteLAC .efpia.eu28
Evaluate - Option 2bTemplate version 1.0Elemental Impurities Product AssessmentElemental Impurity Levels for components– based on Screening data on API Data from the excipient VendorICH Q3D, Current Step 4 version, dated 16 December 2014(Option 2b)RiskProduct Drug Product YDocument IDAssessment 2Formulation InhalationDoses1Components2(/day)Where observed levels LOD, use LOD as observedlevel to represent worst case.Excipient statements made miumSiteCobaltCompanyBatch / )LeadComponentCadmiumTypeAssess (µg/g)CdPbAsHgCoVNiPdPtLiSbBaMoCuSnCrControl Strategy (see Evaluate section, right)APIDPY DrugSubstance0.5DP CompanyManufacturingSite 1DPY-API xcipLactoseMonohydrate24.5Vendor ALAC siteLAC 50.010.030.0010.010.03www.efpia.eu29
Evaluate - Option 2bTemplate version1.0Elemental Impurities Product AssessmentComparison of Elemental Impurity Levels against PDE– based on Screening data on Drug Substance Data from the excipient VendorICH Q3D, Current Step 4 version, dated 16 December 2014 (Option 2b)Product Drug Product YFormulationInhalationDoses (/day)1Document IDRiskAssessment 2Components2Excipient statements made entCadmiumTypeEvaluate (µg/day)SiteCdPbAsHgCoVNiPdPtLiSbBaMoCuSnCrICH Q3D Permitted Daily Exposure yEvaluateBatch / LotNumber30 % Control Threshold inal Evaluated Value (adjusted for 0.000.000.000.000.000.000.00Actual Values (µg/g)(overrides sum evaluation)override override override override override override override override override override override override override override override overrideAction or No actionNo action No action No action No action No action No action No action No action No action No action No action No action No action No action No action No actionAPIDPY DrugSubstance0.5DP CompanyManufacturingSite .5Vendor ALAC 0.000.000.000.000.000.00www.efpia.eu30
Evaluate – Option opperTinChromiumComparison of Elemental Impurity Levels against PDE – based on screening data on ProductSymbolCdPbAsHgCoVNiPdPtLiSbBaMoCuSnCrBatch 1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.10.4 0.1 0.10.3 0.1Batch 2 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.10.4 0.1 0.10.3 0.1Batch 3 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.10.4 0.1 0.10.2 0.1Batch atch atch lement Max DailyIntake 0.0PDE (µg/day)25213151125203001030600.3MDI as % of ake 25 fpia.eu31
Step 3 – Summarize ControlThe overall risk to Patients is very low.ElementClassAdded duringProcess?Present in erObserved Level(µg/day)ControlThreshold(30% of PDE)Summary Table for Submission, based on Existing Controls – Class 1 & 2Actions/Control StrategyCd1NoNegligible riskNegligible riskNoNoNo00.6No further controls requiredPb1NoNegligible riskNegligible riskNoNoNo0.121.5No further controls requiredAs1NoNegligible riskNegligible riskNoNoNo00.6No further controls requiredHg1NoNegligible riskNegligible riskNoNoNo00.3No further controls requiredCo2ANoNegligible riskNegligible riskNoNoNo00.9No further controls requiredV2ANoNegligible riskNegligible riskNoNoNo00.3No further controls requiredNi2ANoNegligible riskNegligible riskNoNoNo01.5No further controls requiredPd2BAPI CatPotentially, butControlledNoNoNoNo00.3No further controls requiredPt2BAPI CatPotentially, butControlledNoNoNoNo00.3No further controls requiredPresent inExcipientswww.efpia.eu32
Summarize ControlThe overall risk to Patients is very low.PackagingComponentsUtilities/WaterObserved Level(µg/day)Control Threshold(30% of PDE)NoNoNo07.5No further controls requiredNegligible riskNegligible riskNoNoNo06No further controls requiredNegligible riskNegligible riskNoNoNo0100No further controls requiredNegligible riskNegligible riskNoNoNo03No further controls requiredNegligible riskNegligible riskNoNoNo09No further controls requiredNegligible riskNegligible riskNoNoNo018No further controls requiredNegligible riskNegligible riskNoNoNo00.9No further controls requiredAdded duringProcess?Negligible riskClassActions/Control StrategyElementPresent inExcipientsManuf.EquipmentSummary Table for Submission, based on Existing Controls – Class 3Present in APILi3NoNegligible riskSb3NoBa3NoMo3NoCu3NoSn3NoCr3Nowww.efpia.eu33
Conclusion As demonstrated by the summary above, the cumulative effect of thematerial specifications, in combination with adherence to the overallcontrol strategy for Drug Product Y Dry Powder Inhaler, 500µg, issufficient to control elemental impurities in the product to within safelevels, below 30% of the proposed ICH Q3D PDE, therefore elementalimpurities are not included in the drug product specification.www.efpia.eu34
Industry Risk AssessmentExample 3Parenteralwww.efpia.eu35
Step 1 - IdentifyProductPowder for reconstitution for IV infusionDose FormPowder in a Type 1 glass vialStrengthTherapeutic Target (Why patients take thisproduct)Dosing Regimen (Frequency & Duration ofdosing)Maximum Daily Dose of Active(s)0.54 g API 1 and 2.4 g API 2Mass of Dosage Unit9.4 g per dayRoute of AdministrationParenteralUSP Monograph for ProductNoSite of ManufactureGMPPacking SiteGMPInfectionMaximum of 3 vials per day1.6 g API 1 and 7.2 g API 2Elements being EvaluatedClass 1Cd, Pb, AS, HgClass 2ACo, V, NiClass 2BTo be confirmed via risk assessmentClass 3Other ElementsLi, Sb, CuTo be confirmed via risk assessmentwww.efpia.eu36
Example 3 – Parenteral,powder for reconstitution for infusion The vial is reconstituted withcommercially available infusion fluid. TheComponentFunctionalityAmountper vial(g)API 1Drug substance0.54SyntheticAPI 2Drug /mineralreconstituted vial is then further dilutedwith infusion fluid prior to administrationby intravenous infusion.The infusion fluid is outside the scope ofTypethis risk assessment.www.efpia.eu37
Product Information – drug product manufacturePowder blendingVial fillingNitrogen overlayEvaluation process not just datadrivenCan be based on first principlesSection 5.2 – Risk can be reduced throughprocess understanding / equipmentselection / qualification and GMPprocesses.StopperingCrimpingSecondary packagingwww.efpia.eu38
Product Information – packaging Drug Substance packagingLow Density Polyethylene (LDPE)/Laminate bag. Drug Product Intermediate Powder Blend packagingLow Density Polyethylene (LDPE)/Laminate bag. Drug Product packagingClear, Type I glass vial with a bromobutyl rubber stopper with a fluorinated polymercoating and aluminium flip-off over seal.www.efpia.eu39
Step 1 – IdentifyIdentify Review API, excipient and drug productmanufacturing process to identify knownand potential sources of ElementalImpuritiesEvaluate Collect predicted and/or observed levels ofelemental impurities Compare data with the establishedPermitted Daily ExposureSummarizeControl Summarize and document the riskassessment Identify additional control requirements, ifrequired, to ensure PDE is met In this example the review of the drugsubstance and drug product manufacturingprocess was facilitated by a questionnairedesigned to aid identification of any high-risksources of elemental impurities for furtherattention. Potential sources of EIs are capturedalongside the elemental impurities ofconcern.www.efpia.eu40
IdentifySimple templated process for identification of high-riskswww.efpia.eu41
Step 2 - Evaluate Based on the templatedMetal impurities included in analyticalscreening‘Intentionally added’Environmental metalsmetalse.g. catalysts/reagentsPotential source ofmetal impuritiesNo. of batches to beanalysedAPI 1A minimum of3 commerciallyrepresentativebatches.NoneClass 2B: PdAPI 2NoneNoneNoneSodium CarbonateA minimum of3 commerciallyrepresentativebatches.Class 1: As, Cd, Hg, PbClass 2A: V, Co, NiClass 3: Li, Sb, CuNoneassessment – screeningrequirements were defined. NB – The risk associatedwith the mined/mineralexcipient, was based onabsence of data to effectivelyquantify risk.Section 9 – The determination of EIs should beconducted using appropriate procedures suitable fortheir intended purposeSection 5.6 - 3 production or 6 pilot scale lotswww.efpia.eu42
The Big 4, Class 1 metals are not as ubiquitous as feared inmaterials used in the Pharma IndustryStep 2 – Evaluate No EIs 30% PDE across API 1 and excipient batches testedSampleAPI 1BatchnumberAsPbCdHgVCoNiLiSbCuPd10.220.230.21 0.05 0.1 0.05 0.05 0.1 0.10.4 0.1 0.10.52 0.05 0.1 0.05 0.05 0.1 0.10.2 0.1 0.1 0.13 0.05 0.1 0.05 0.05 0.1 0.10.5 0.1 0.10.4Option 2A limit (µg/g)0.160.530.210.161.10.532.1279.510.61.130% Option 2A diumcarbonatewww.efpia.eu43
Step 3 – Summarize Control - ActionsThe overall risk to Patients is very low.Elementalimpurities witha relativelyElementhigh(if used in systemsMaximumelementalimpurity dailyintake µg/dayAcceptablevariability /day(30% PDE)ActionAsNoNegligiblelevelsNoNoYesno further controlsrequiredCdNoNegligiblelevelsNoNoYesno further controlsrequiredHgNoNegligiblelevelsNoNoYesno further controlsrequiredPbNoNegligiblelevelsNoNoYesno further controlsrequiredwww.efpia.eu44
Step 3 – Summarize Control - ActionsElementElementalimpurities witha relatively high Manufacturin(if used in the environmental g d y dailyintake µg/dayThe overall risk to Patients is very low.Acceptablevariability /day(30% PDE)ActionNiNoNegligible levelsNoNoYesno further controlsrequiredCoNoNegligible levelsNoNoYesVNoNegligible levelsNoNoYesPdYesNegligible levelsNoNoYesno further controlsrequiredno further controlsrequiredno further controlsrequiredLiNoNegligible levelsNoNoYesno further controlsrequiredSbNoNegligible levelsNoNoYesno further controlsrequiredCuNoNegligible levelsNoNoYesno further controlsrequiredwww.efpia.eu45
Option 3 Also an option Examples presented all involve component assessment. Can also utilize Option 3 – Test Final Drug Product: Advantages : less time and resource consuming no need to getinformation from excipient suppliers/process etc. ( or an alternativewhen they are not available ) If the outcome of the DP risk assessment is elemental impurities 30% PDE, acomponent risk analysis approach may then be set up to identify route cause.www.efpia.eu46
Marketing Application – Key PrinciplesPerformed in accordance with principles outlined in ICH Q3D – Section 6 Will typically be presented in DP specification justification P5.6 Cross referenced to API section where relevant S4.5.Summary of risk assessment Key aspects of process Key risks identifiedSummary of control strategy Defined controls (limits and method) for specific EI as necessary Risk assessment and / or data supports that (other) EIs will not arise at levels 30% of target thresholdwww.efpia.eu47
Clinical ApplicationsICH Q3D SCOPE – Section 2 “This guideline does not apply to DP used during clinical research stages ofdevelopment” Patient Safety is assured during the clinical research stages as EIs are controlledby Control of API specifically control of metal catalysts Use of pharmaceutical grade Excipients Formal risk assessment initiated when commercial formulation and process isdefined.www.efpia.eu48
Key Learnings The overall risk to Patients is very low.– Drug product / API / excipient data generated to date has found very few issues.– The Big 4, Class 1 metals are not as ubiquitous as feared in materials used in the Pharma Industry. There are multiple ways to conduct a risk assessment - Section 6– The basic process and considerations are well aligned across product manufacturers.– Everyone does it slightly differently. Evaluation process not just data driven– Can be based on first principles. Prior Knowledge can form an important part of the risk assessment– Literature, test data from related materials, databases etc. The theoretical mathematics work– Components that make up a small part of the daily dose are unlikely to “tip-the-balance”. Control Strategy should be based on the outcome of the risk assessment– If the risk assessment demonstrates that EIs are not present then routine QC testing of drugsubstance, excipients or drug product for environmental elements should not be performed.www.efpia.eu49
Key Learnings (cont.) Appreciate the Analytical Challenges Validation should be fit for purpose. ICP-MS is not a “magic answer” Specific challenges
Summarize and document the risk assessment Identify additional control requirements, if required, to ensure PDE is met . www.efpia.eu 5 Industry Risk Assessment Example 1 Synthetic API – tablet . www.efpia.eu 6 Industry Risk Assessment Example 1 – Oral Solid Dose Product .
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